The TSC/Rheb/mTOR signaling pathway plays important roles in protein synthesis, growth and cell cycle progression in response to nutrients, energy and growth factors such as insulin and insulin like growth factor. Overactivation of this signaling pathway is detected in a variety of human cancers and rapamycin, an inhibitor of mTOR, is being evaluated in clinical trials. Our recent work demonstrated that a single amino acid change can confer constitutive activation. More recently, we have made an important discovery that activating mutants of mTOR can be identified in human cancer genome database. In this application, we will focus on these mTOR mutants and ask first whether these mutants exhibit transforming activities. We will then carry out experiments aimed at gaining insight into the mechanism of activation of mTOR by the mutations. Finally, we will use fission yeast as a system amenable to genetic analysis to gain further insight into the mechanism of activation of the TOR signaling. PUBLIC HEALTH RELEVANCE: The mTOR signaling plays critical roles in growth and proliferation of mammalian cells. Deregulation of this signaling pathway causes cancer and genetic disorders. We will identify and characterize mutations in mTOR that confer constitutive activation.